The periodic fluctuations in numbers of red grouse (<I>Lagopus lagopus scoticus </I>(Lath.)) populations in Scotland and northern England remain a puzzle to population ecologists despite sustained research. Other workers have suggested that territoriality, philopatry and kin selection, as expressed in the differential behaviour between kin and non-kin, can, through their effects on the efficiency of space use, combine to cause cyclic dynamics. However, since the first preliminary formulation of the hypothesis in 1990, little modelling work has been done on the subject. In this thesis, I present a series of models which explore the plausibility of the kin-selection hypothesis for red grouse populations under different assumption regimes. I first develop, analyse and validate a simple, deterministic model using functions of age structure as indexes of the social and, due to philopatry, spatial attributes of the population. A control version of the model is incapable of cyclic dynamics, while a modification, containing the assumed effects of kin selection, produces cycles of realistic period and amplitude. Parameterisation of the model with field data from two studies in north-east Scotland yields output which resembles the observed dynamics. A more detailed study of the possible effects of kin selection and philopatry on individual requirements for space yields a parameterised response function which is then used to study the dynamics of individual family clusters. A model of the relatively short-term process of family cluster formation demonstrates that continuous changes in crowding may have a discontinuous effect on the ability of clusters to form. A socially and spatially explicit simulation model is finally developed to examine the relative importance of these factors in the long-term dynamics. Based on its results, I conclude that spatial heterogeneity in the activity of animals, caused by clustering, is sufficient to produce cycles and that variations in territorial requirements due to differential behaviour between kin and non-kin can have a secondary, amplifying role in the process.

Important ecological processes happen over long periods of time and at the landscape scale. Effective conservation of biodiversity and management of natural resources and ecosystem services requires an understanding of these processes. Unfortunately, it is often impractical to conduct appropriate long-term, landscape-scale studies. Modelling offers an alternative approach. Complete ecosystems are too complex to model practically, but simulations of simplified systems provide useful insights of practical value. LandBaSE-P is an individual-based model for Puya hamata that provides information about impacts of fire on ecological processes in the páramo of the Reserva Ecológica El Ángel, Ecuador. Puya hamata is a flagship plant affected by fires and plays a key role in a number of ecological processes. This research found Puya hamata germinated much more frequently after fires, can form large aggregations of single recruitment cohorts, suffers very low mortality (with and without fires) once established, and lives up to 28 years. The spatial aggregation of Puya hamata plants reduced effective reproductive output, consistent with the theory that pollinator behaviour around large groups of Puya plants reduces cross-pollination, leading to inbreeding depression and poorer seed viability and germination. Puya hamata’s population structure can be an indicator of recent fire regime. LandBaSE-P simulations showed that population size is not affected by rare, long-distance seed dispersal. However, in the simulations of páramo grasslands, Puya relative germination is maintained in high numbers by burning. Puya hamata has an important role in ecology and biodiversity. The model LandBaSE-P is a complementary tool for conservation and sustainable land management. This thesis shows how fieldwork combined with laboratory studies and modelling, can provide a good understanding of complex dynamics of real-world populations, and generate ideas for management and future research.

No description available.

I used 8 years of mark-recapture data to test alternative hypotheses about the relative influence of winter climate, social structure, and life history on survival, reproduction, and population dynamics of hoary marmots (Marmota caligata) in the southwest Yukon. Climate, characterized by the mean winter Pacific Decadal Oscillation index (PDO), was strongly related to juvenile survival, more weakly linked with adult survival and fecundity, and did not appear to influence breeding probability. Group social structure had little influence on population dynamics. Variation in adult and juvenile survival affected the population growth rate more strongly than fecundity or breeding probability, but the relative influence of life history parameters changed from year to year. Comparisons between hoary marmots and other alpine mammals indicated that the average environment to which an animal is adapted, the strategies employed to survive winter, and life history constraints may all affect demographic sensitivity to winter climate. / Ecology

Changes in climate shape biological populations. They can alter spatial distributions, the timing of life history events, and even the species themselves. We are now experiencing a period of rapid directional climate change, alongside seasonal fluctuations. This thesis investigates temporal changes in life history events, phenology, as a climate response. I explore the causes and population level consequences of change in breeding phenology of two wild bird populations from Wytham Woods, UK. I test how great tits (Parus major) and blue tits (Cyanistes caeruleus) achieve temporal synchrony between the peak demands of their breeding and the peak abundance of their prey species (winter moth caterpillars - Operophtera brumata) in an inter-annually variable environment. I demonstrate great tit (Parus major) incubation behaviour fine-tunes the timing of hatching in response to ambient temperatures right up until hatching (Chapter two). Temperatures within the nest box, however, appear to play little role in the breeding phenology of blue tits (Cyanistes caeruleus) (Chapter two). I discuss the merits and limitations of statistical approaches for cue identification (Chapter six), finding the method and time period of data used both affect the cue identified and predictive accuracy. The second part of this thesis explores the influence of a directionally changing environment on great tit phenology. I use an integral projection model (IPM) to predict population dynamics over the 21^st century, showing that if the cues used by both interacting species change sufficiently closely, temporal synchrony can be maintained through both phenotypic plasticity and micro-evolution (Chapter 5). However, if the cues diverge mismatch will arise (Chapter 5) causing population declines when certain thresholds are passed (Chapter 4). This work contributes to understanding how phenological synchrony is achieved, how it might change in the future, and its population impacts. In Wytham Woods it appears that great tits have a great deal of flexibility in multiple components of their breeding cycle, allowing them to retain synchrony with their caterpillar prey in a fluctuating environment. These birds are relatively resilient to negative phenological impacts from climate change. Only if the cues used by the predator and prey completely diverge do we predict consistent declines in population size during this century.

The Vestibulo-Ocular Reflex (VOR) produces compensatory eye movements in response to head and body rotations movements, over a wide range of frequencies and in a variety of dimensions. The individual components of the VOR are separated into parallel pathways, each dealing with rotations or movements in individual planes or axes. The Horizontal VOR (hVOR) compensates for eye movements in the Horizontal plane, and comprises a linear and non-linear pathway. The linear pathway of the hVOR provides fast and accurate compensation for rotations, the response being produced through 3-neuron arc, producing a direct translation of detected head velocity to compensatory eye velocity. However, single neurons involved in the middle stage of this 3-neuron arc cannot account for the wide frequency over which the reflex compensates, and the response is produced through the population response of the Medial Vestibular Nucleus (MVN) neurons involved. Population Heterogeneity likely plays a role in the production of high fidelity population response, especially for high frequency rotations. Here we present evidence that, in populations of bio-physical compartmental models of the MVN neurons involved, Heterogeneity across the population, in the form of diverse spontaneous firing rates, improves the response fidelity of the population over Homogeneous populations. Further, we show that the specific intrinsic membrane properties that give rise to this Heterogeneity may be the diversity of certain slow voltage activated Potassium conductances of the neurons. We show that Heterogeneous populations perform significantly better than Homogeneous populations, for a wide range of input amplitudes and frequencies, producing a much higher fidelity response. We propose that variance of Potassium conductances provides a plausible biological means by which Heterogeneity arises, and that the Heterogeneity plays an important functional role in MVN neuron population responses. We discuss our findings in relation to the specific mechanism of Desynchronisation through which the benfits of Heterogeneity may arise, and place those findings in the context of previous work on Heterogeneity both in general neural processing, and the VOR in particular. Interesting findings regarding the emergence of phase leads are also discussed, as well as suggestions for future work, looking further at Heterogeneity of MVN neuron populations.

Sudden cardiac death represents one of the leading causes of death worldwide, with the majority of these deaths caused by arrhythmias derived from ischæmic events. However, the mechanisms leading from ischæmia to re-entry, arrhythmia and eventual death are poorly understood. Furthermore, variability in the action potential of cardiac tissue, while important in determining arrhythmic risk, is only recently being addressed in computational modelling, with little known about the causes and mechanisms underlying it, nor regarding its evolution in response to pathological conditions such as ischæmia. This dissertation investigates the causes of variability in the repolarisation of the action potential of the rabbit ventricular myocyte, and the response of this variability to ischæmia. The effect of variability in ion channel conductances is investigated by means of a complete search of the parameter space revealed by simultaneous variation in multiple parameters describing ion channel conductances in computational models of the rabbit ventricular action potential. Rabbit data and models are used in this thesis due to the similarities to human data, both in terms of electrophysiology generally, and the response to ischæmia specifically. The response of two different model frameworks is assessed to determine similarities and differences between model frameworks that are designed to reproduce the same system. Those models producing action potential durations that fall within an experimentally derived range at multiple pacing rates are used to define model populations that thus reproduce experimental variability in repolarisation. These model populations are used to investigate the effects of ischæmic conditions on population variability. Variability is measured not only for action potential duration, but also for other biomarkers commonly implicated in the development of re-entry. The work presented in this dissertation is significant for: (1) presenting a comprehensive study of the effect of simultaneous variation in ion channel conductances, with details regarding the interactions between conductances and how these interactions change depending on the pacing rate; (2) detailed examination of the differences between two models of the same system; (3) production of the largest extant populations reproducing experimentally observed variability in action potential duration; (4) the first time model populations have been used to investigate the effects of ischæmia on variability.

Metapopulation ecology has developed to explain the population dynamics that occur in spatially structured landscapes. In this study, I combined an empirical laboratory approach, using metapopulation microcosms of Callosobruchus maculatus and its endospecific parasitoid Anisopteromalus calandrae, with mathematical population models in order to investigate several fundamental metapopulation processes. Population dynamics in these systems can be studied at two scales; the local patch-wise scale and the regional metapopulation scale. Here I demonstrate that in both homogeneous and heterogeneous landscapes knowledge of local scale demographic processes is necessary in order to understand regional metapopulation dynamics. The differences in the rate and net direction of dispersal between patches as a result of the permeability of the matrix in homogeneous systems and density-dependent dispersal in heterogeneous systems were also explored. Metapopulation dynamics rely on a balance between local extinctions and recolonisations. Therefore, increasing local mortality rates is likely to be detrimental to the persistence of the system. Here, the impact of several common harvesting strategies on the persistence of a host-parasitoid metapopulation was examined. Contrary to expectation I discovered that harvesting in these systems increased both local and regional population sizes. The increased population size as a result of increased mortality was explained in terms of a hydra effect, where harvesting relaxed density-dependence acting on local host populations. The results presented in this thesis are relevant for the monitoring, management and conservation of natural metapopulations and the development of sustainable harvesting strategies in structured landscapes.

Abstract The global aims of this thesis were: to evaluate if an individualised dose strategy for enoxaparin, based on lean body weight and renal function, resulted in a reduction in the prevalence of bleeding and bruising events when compared to conventional dosing; to further understand the dose-exposure-response relationship for enoxaparin using population pharmacokinetic-pharmacodynamic (PKPD) modelling. This thesis comprises seven chapters: an introduction to the current knowledge and literature pertaining to low-molecular-weight heparins (LMWHs), in particular enoxaparin; five research chapters; and a discussion. Each of the five research chapters consists of a manuscript that has been published in, accepted or submitted for peer review in a scientific journal. Preceding each chapter is a synopsis of the important features of the publication. Supplementary information that supports the findings of the publication, but could not be included in the publication, is provided at the end of the chapter. Appendices relevant to each chapter are located at the end of the thesis. Chapter one is the introduction to this thesis. It commences with an overview of the LMWHs, their mechanism of action, customary uses, licensed doses and adverse effects. There is a brief introduction to renal function and body composition; physiological factors that influence the disposition of LMWHs. As much of this thesis is centred on defining the dose-exposure-response relationship for enoxaparin, there is a critique of the existing literature relevant to each segment of this relationship, namely: dose-exposure, exposure-response and dose-response. To conclude this chapter there is a review of pharmacostatistical models and population modelling, followed by an appraisal of population PK and PKPD models that have previously been developed for enoxaparin, including the two key publications that are critical to this thesis. These two papers were the first to fully describe the dose-exposure relationship for enoxaparin in subjects with renal impairment and obesity. It is from these studies that the individualised dosing strategy, explored throughout this thesis, was developed. The specific aims of the five research chapters are then stated. Chapter two describes a confirmatory, randomised controlled trial (RCT) to compare an individualised dose of enoxaparin to conventional, label based dosing. The RCT was conducted at a major tertiary teaching hospital over an 18 month period. The primary endpoint was the prevalence of overt bleeding events and the secondary endpoint a combination of bleeding or major bruising events. A time-to-bleeding event analysis (Kaplan-Meier) was used and markers of effectiveness such as mortality and readmission were assessed out to 30 days post recruitment. Bleeding and bruising data, along with anti-Xa (aXa)-concentrations were collected for use in additional research described in chapters four and five. Chapter three details the evolution, progression and contemporary knowledge of drug dosing based on body composition and focuses on dosing in obese subjects with cardiovascular disease. The concept of dose-individualisation is explored in this chapter with reference to the methods used to normalise drug exposure across the spectrum of body compositions. Subsequently, there is a review of body size descriptors, such as lean body weight, that are used to scale dosing in the obese. Enoxaparin is used as a motivating example, with reference to data presented in Chapter two of this thesis. There is also a discussion about the type of research designs that are required to maximise information about PK parameters. This chapter was published within a book chapter which was intended for clinical practitioners in the discipline of cardiology. Chapter four is focused on the development and evaluation of population PK and PKPD models to describe the time-course of effects for enoxaparin. A population PK model linked to a proportional-odds model was used to describe the severity of an adverse event as a function of exposure and demographic variables. The final model was used to explore the likely occurrence of bleeding and bruising events in patients with obesity and / or renal impairment dosed using either the individualised or conventional dose strategies from Chapter two. Chapter five describes a study that was undertaken to evaluate the ability of the individualised dosing strategy to achieve and maintain aXa-concentrations within the therapeutic range (500 to 1000 IU L-1), by comparison to conventional dosing. As the confirmatory study focused on the prevalence of adverse events there was no assessment of the therapeutic capability of the dose strategies however, as aXa-concentrations were collected using a sparse design during the confirmatory study, the two dose strategies could not be compared using observed data. Therefore, the population PK model developed in Chapter four was used to predict individual subject concentration-time profiles to 120 hours of enoxaparin therapy. The time spent in the therapeutic, supra-therapeutic and sub-therapeutic ranges was computed for each subject and the dosing strategies statistically compared. This study also allowed the evaluation of the results from Chapter two from a dose-exposure perspective. Chapter six of this thesis describes a survey. The aim of this survey was to gain an understanding of how dosing strategies of enoxaparin vary in four countries, investigate if clinicians are prescribing according to the Product label, and determine the methods used to dose-individualise enoxaparin. In doing so, individual hospitals in the international community will be able to compare, critique or benchmark their own strategies to peer hospitals, as well as the current literature. The publication arising from this survey would assist in the dissemination of knowledge gained from the earlier chapters of this thesis. Chapter seven is the final discussion and conclusions of the thesis along with prospects for future research.

Optimal pharmacotherapy requires an understanding of the dose-exposure (pharmacokinetics or PK) to response (pharmacodynamic or PD) relationship. Little is known about the influence of obesity on this dynamic system as PK studies in obesity have been largely descriptive rather than explanatory. This has led to a paucity of dosing guidelines for the obese, and arbitrary dose selection in the clinic. There is a need to quantify the impact of obesity on drug clearance (CL) to ensure that exposure is matched across patients of different body compositions, thereby improving therapeutic outcomes and minimising adverse events. The global aim of this thesis was to use prior published data and new clinical trial data to understand how body composition impacts upon drug CL and renal function, and to determine how clinical study design influences the identification of these relationships. Chapter 2 of this thesis determined if conventional body size descriptors that have been used to scale drug doses to body size were appropriate. In the clinical setting, a body size descriptor commonly used for determining dose requirements is total body weight (WT), based on the assumption that physiological function and PK parameters vary according to body size. However, dosing algorithms based on WT might be unsuitable for the obese due to their altered body composition which, if inaccurate, could ultimately lead to overdoses. Alternative body size descriptors such as body surface area and ideal body weight have been used, but are limited when extrapolated to obese patients as they do not take into account the covariates required to describe differences in body composition between individuals. In contrast, it was demonstrated that lean body weight (LBW), as derived by Janmahasatian et al, had the potential to scale CL across a wide range of body compositions. This literature review and systematic analysis of previously published obesity data led to the proposal of a hypothesis that body composition is sufficient to explain the influence of obesity on drug CL and that dosing for obese patients should be based on LBW. When conducting clinical studies, the selection of an appropriate body size descriptor for scaling doses across individuals of different body compositions can be aided by a study design that allows for the identification of parameter-covariate relationships which are transportable to the obese. Chapter 3 of this thesis quantified the probability of identifying these parameter-covariate relationships as a function of differing study designs. Demographics were generated using a multivariate lognormal covariate distribution with truncation at different WT limits under both a non-stratified and stratified design. PK data were simulated from a 1-compartment, first order input, first order elimination model with LBW as the covariate on CL, termed the ‘True Model’. The ‘False Model’ had WT as the covariate on CL. Both models were fitted to the simulated data and the preferred model was selected based on the difference in objective function values. Each design was evaluated under differing magnitudes of random effects, as well as under a D-optimal sparse sampling scheme. It was shown under a simulation platform that the use of stratification and a wide covariate range enhanced the probability of selecting the true covariate from two competing covariate models. The aforementioned findings regarding LBW and stratification were used to design a new clinical study investigating the influence of obesity on renal drug elimination pathways. This work forms Chapters 4 and 5 of this thesis. Non-obese and obese healthy volunteers were recruited using a study design stratified for LBW. These subjects were administered a combination of four renal markers for the simultaneous assessment of various renal processes. One of the renal markers was para-aminohippuric acid (PAH), which provides an estimation of renal plasma flow (RPF). A population PK model was developed for PAH, which revealed that body size alone was insufficient to explain variability in RPF across healthy individuals of a large range of body compositions, although LBW emerged as the preferred covariate (p=0.053) among the body size descriptors tested. This weak covariate effect was in contrast with prior research supporting the use of LBW in normalising the effect of obesity on glomerular filtration rate (GFR), implying that body composition could play a greater role in influencing GFR than RPF. This thesis has applied new methods to the design of drug CL studies in obesity, and offered results and future directions to maximise the information gained from such clinical studies. A better understanding of alterations in PK and physiological function arising from changes in body composition should aid in optimising dose adjustments for obese patients, which is of great importance given the increasing prevalence of obesity in today’s society.